The need for biomaterials in orthopaedic and dental applications has increased as the world population ages. A significant amount of research into biomaterials for orthopaedic and dental uses has attempted to address the functional criteria for orthopaedic and denial reconstruction within the human body. The materials which have become available for such uses have improved in recent years. All such materials must be biocompatible, however, and the degree of biocompatibility exhibited by materials which are candidates for such use is always a major concern. Biomaterials useful for orthopaedic and dental reconstructions must have high strength, must be able to be immediately affixed to the situs for reconstruction, must bond strongly to bone, and must give rise to strong, highly resilient restorations.
Among the materials which have been used for orthopaedic and dental restorative purposes are bone cements based upon acrylic species such as polymethyl methacrylate (PMMA) and related compositions. Such materials usually are capable of convenient delivery to the site of restoration and can be formed as to be moldable and to have reasonable degrees of affinity for bony tissue. PMMA cements, however, lack bioactivity and the ability to generate a chemical bond to bone and new bone tissue formation. The inertness of such restoratives leads to micromotion and fatigue over time with attendant aseptic loosening. Additionally, the polymerization of PMMA-based materials can give rise to significant exothermicity which can lead to localized tissue necrosis and inflammation. Moreover, residual methyl methacrylate monomer can leech into surrounding tissue leading to site inflammation and implant failure. Implants formed from PMMA-based materials can also give rise to particulate debris, inflammation, and failure. PMMA polymeric structures are generally two-dimensional and limited as to strength.
Bone grafts using bioactive glasses and calcium phosphates, collagen, mixtures and the like nave good biocompatibility and give rise to bone tissue formation and incorporation in some cases. However, prior graft materials lack the desired load bearing strength and are generally technique sensitive.
Prior attempts to improve such bone grafting material through the development of self-setting calcium phosphate cements as well as glass ionomer bone cements have shown promise. Both materials can be bioactive in some cases and both can exhibit considerable strength. Glass ionomers, in particular, have enjoyed success in dental applications. However, most of the strengths of glass ionomer composites is achieved by reacting a fluoro-aluminosilicate glass with a polyalkenoic polymer matrix. Carboxyl functionalities exist on the polymer backbone, which functionalities chelate with ions in the surface bone material. The usual time for a surface active biomaterial to form an inner active layer with inner tissue is from six to eight weeks. If the material's function relies upon this interactive biolayer rather than its inherent strength, the required reaction time can lead to premature failure of the material.
A number of different glasses, glass-ceramics, and crystalline phase materials have been used, either alone or in combination with acrylic polymerizable species, and other families of polymers, for restorative purposes. These include hydroxyapatite, fluorapatite, oxyapatite, Wollastonite, anorthite, calcium fluoride, agrellite, devitrite, canasite, phlogopite, monetite, brushite, octocalcium phosphate, Whitlockite, tetracalcium phosphate, cordierite, and Berlinite. Representative patents describing such uses include U.S. Pat. Nos. 3,981,736, 4,652,534, 4,643,982, 4,775,646, 5,236,458, 2,920,971, 5,336,642, and 2,920,971. Additional references include Japanese Patent No. 87-010939 and German Patent OS 2,208,236. Other references may be found in W. F. Brown, "Solubilities of Phosphate & Other Sparingly Soluble Compounds," Environmental Phosphorous Handbook, Ch. 10 (1973). All of the foregoing are incorporated herein by reference to provide disclosure, inter alia of prior restorative materials and methods and compositions which may be included in the compositions and methods of the invention, as well as methods which may be employed as part of or ancillary to the invention.
In addition to the foregoing, certain animal-derived materials, including coral and nacre, have also been used in biomaterials for restorative purposes.
U.S. Pat. No. 4,239,113 to Gross et al. reports a pliable, moldable acrylic-based bone cement reinforced with from 15 to 75% by weight of a bioactive glass together with between 1 and 10% by weight of vitreous mineral fibers. The disclosed function of the glass fillers and fibers is to impart mechanical strength to the acrylic matrix, however this advantage diminishes as the fibers degrade over time in the body. Most of the problems associated with the use of polymethyl methacrylate still exist in the materials disclosed by Gross.
Vuillemin et al. in Arch. Otolygol. Head Neck Surg. Vol 113 pp. 836-b 840 (1987) introduced different bioactive fillers such as tricalcium phosphate and bioceramic A.sub.2 into bisphenol-A-diglycidyl methacrylate (bis GMA) polymerizable through the action of peroxide systems such as benzoyl peroxide mixed with amines. Use in human subjects for successful treatment of a right frontal sinus and a supraorbital edge was shown in a frontobasal skull fracture. Both examples were primarily non-load bearing, however.
Two component, resin composites containing both salicylates and acrylates, cured through a calcium hydroxide cement reaction is described by Walton in U.S. Pat. No. 4,886,843. The use of calcium hydroxide as a filler results in Ca.sup.2+ ion release for the remineralization of dental tissues while filling tooth restorations. Adherence to tooth structure was shown together with maintenance of strength and permeability for the reaction of the calcium hydroxide filler.
Kokubo et al. in U.S. Pat. No. 5,145,520 discloses a powder-liquid mixture yielding a bioactive cement. Fine glass powder comprising a apatite-Wollastoiiite glass-ceramic, is reacted with an aqueous solution of ammonium phosphate. The resulting, hardening cement was employed to repair bone and as a dental restorative cement. The cement was said to harden quickly to a high strength material with no heat generation during its setting.
Sugihara et al., in U.S. Pat. No. 238,491, discloses a powder-liquid hardening dental material. This material uses tricalcium phosphate or tetracalcium phosphate as a main constituent together with a hardening liquid comprising of at least one inorganic acid such as acetic acid. An addition of collagen is used to aid in biocompatibility and hydroxyapatite formation. One disclosed goal is biocompatibility together with chemical bonding and space filling of adjacent tissues.
PCT document WO 93/16738 --Yamamro et al. describes a bioactive cement deriving from a bioactive glass-filled resin matrix composite. The class is a non-alkali-containing calcium oxide-silica-P.sub.2 O.sub.5 -magnesium oxide-calcium fluoride loaded into a resin matrix., bisphenol-A glycidyl dimethacrylate, polymerized in two separate pastes, one containing benzoyl peroxide and one N, N-dimethyl-p-toluidine. The interaction of the fillers with the resin was said to be significant, giving rise to a good physiological environment for the achievement of bioactive composites having high strength, low heat generation, and good bonding capability.
Saito et al., in Biomaterials Vol 15 No. 2 (1994), used bisphenol-A glycidyl dimethacrylate together with amine-peroxide catalyst as a resin matrix to be filled with hydroxyapatite granules having average size of approximately 2 micrometers. This material was said to show good strength as a bone cement (compressive strength of 260 MPa), along with good bioactivity and bone formation in the bonding of femoral condyles of rabbits after eight weeks. The cement was also said to have a low exotherm of polymerization.
Zamora et al., in an abstract submitted for the Spring 1995 meeting of the American Chemical Society entitled Bioglass Reinforced Dental Composites: Thermal Mechanical Properties, describe a heat polymerized bisphenol-A glycidyl dimethacrylate matrix reinforced with Bioglass.TM. (described below). It was suggested that the bis GMA resin matrix gives significantly lower exotherms of polymerization and polymethyl methacrylate.
Tamura et al., in Journal of Biomedical Materials Research Vol. 29 pp 551-559 (1995), discloses the effect of the amount of filler loading an a bioactive bone cement. Apatite-Wollastonite glass-ceramic filler, together with a bisphenol-A glycidyl dimethacrylate matrix resin was employed in weight ratios of 30, 50, 70, and 80%. Animal studies were said to show that bioactivity increases as the bioactive filler was increased, however the mechanical properties did not necessarily follow the same trend.
Dickens-Venz et al., in Dent. Mater. Vol. 10 pp 100-106 (1994), report on the physical and chemical properties of resin-reinforced calcium phosphate cements.
Meechan et al., in British Journal of Oral and Maxillofacial Surgery Vol. 32 pp. 91-93 (1994), disclose a pilot study analyzing the adhesion of composite resins to bone using commercially available dental materials.
Roemer et al., in U.S. Pat. No. 4,396,476, disclose interpenetrating polymer networks in hardenable compositions for a number of uses including the filling of teeth and bone.
U.S. Pat. No., 4,369,262 --Walkowiak et al. discloses dental materials based upon filled cross-linked plastics together with polymerizable binders.
U.S. Pat. No. 4,110,184 --Dart et al. discloses photocurable dental filling compositions based on modified, filled acrylic polymerizable materials.
Bioglass.TM. is believed to be described in U.S. Pat. No. 4,851,046 --Low et al. Low et al. describe a biocompatible glass, known to those skilled in the art as 45S5 bioactive glass, in particular particle size S distributions to facilitate admixture with blood for repair of periodontal defects. Bone tissue ingrowth peripheral to the repair is disclosed. The materials disclosed by Low et al. are not significantly load bearing, however.
U.S. Pat. No. 5,204,106--Schepers e(t al. discloses improved methods for forming osseous tissue from bioactive glass such as 45S5 glass. Critical particle sizes permit osteogenesis throughout a restoration. The disclosed compositions are not highly load bearing.
While a number of materials have been shown to be useful for the filling of bone and for use in restorative dentistry, there is still a significant need for improved materials for such uses. Thus, there remains a long-felt need for restorative compositions comprising resin matrixes together with bioactive fillers which have the desired combination of delivery viscosity, setting conditions, setting strength, and bioactivity, combined with great overall strength and long-term compatibility with bone and other tissue. It is also greatly desired to achieve stable, strong, biocompatible restorations in a short time period, shorter than the up to eight weeks which can be required with prior materials.
It is, therefore, a principal object of the present invention to provide improved bone restorative materials having immediate physical strength and biocompatibility.
A further object of the invention is to provide load bearing bone bonding composite materials for use in diverse restorative circumstances within the human body.
Yet another object of the invention is to provide materials having rapid adherence to implants and bone tissue together with the achievement of elastic moduli which are close to the modulus of bone.
A still further object is to achieve bone bonding composites which can give rise to an active resin-calcium oxide-phosphorus oxide gel layer which is capable of enhancing the toughness and long term mechanical stability of restorations employing such materials.
Another object of the invention is to improve implant fixation in dentistry and orthopaedics through the improved physical and physiochemcial relationship of materials of the present invention, natural bone, and implant materials.
A further object of the invention is to incorporate certain drugs into the compositions hereof so as to confer the benefits of such drugs upon the situses of restoration employing such materials.
Still another object is to provide hardened, shaped bodies of bioactive material for orthopaedic and dental use.
It is also an object of the invention to provide bone grafting materials and cements which are capable of immediate placement together with concomitant load bearing ability as well as ensuing bioactivity giving rise to the formation of natural bony tissue.
Other objects will be apparent from a review of the specification and attendant claims.